Method for producing optically active cycloalkylidenebisoxazoline compound and intermediate thereof

ABSTRACT

It is provided to an optically active cycloalkylidenebisamidoalcohol compound represented by the formula (3): 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 1  represents a C1-6 alkyl group, an optionally substituted phenyl group, an optionally substituted aralkyl group or a hydrogen atom, or two R 1 s, which are bonded to the same carbon atom, are bonded to form a ring together with the carbon atom to which they are bonded, R 2  represents a C1-6 alkyl group, an optionally substituted aralkyl group or an optionally substituted phenyl group and * represents an asymmetric center, a method for producing it and a method for producing an optically active cycloalkylidenebisoxazoline compound represented by the formula (4): 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             wherein R 1 , R 2  and * are as defined above, using thereof.

TECHNICAL FIELD

The present invention relates to a method for producing an opticallyactive cycloalkylidenebisoxazoline compound which is an importantcompound as a ligand of an asymmetric synthesis catalyst.

BACKGROUND ART

An optically active cycloalkylidenebisoxazoline compound has been knownas a component of copper bisoxazoline catalyst for asymmetric synthesisof an intermediate of agricultural chemicals and pharmaceuticals such assynthesized pyrethroid type insecticides. As methods for producing theoptically active cycloalkylidenebisoxazoline compound, a method forreacting a 2,2-methylenebisoxazoline compound, which is obtained by thereaction of the corresponding optically active aminoalcohol and amalonimidate, with a alkyl dihalide such as 1,2-dibromoethane in thepresence of a strong base (e.g. Non-patent document 1). However, it isnot always satisfied in the overall yield.

Non-patent document 1: J. Org. Chem., 65, 5875 (2000)

DISCLOSURE OF THE INVENTION

According to the present invention, an optically activecycloalkylidenebisoxazoline compound can be efficiently produced.

That is, one of embodiments of the present invention relates to anoptically active cycloalkylidenebisamidoalcohol compound represented bythe formula (3):

wherein R¹ represents a C1-6 alkyl group, an optionally substitutedphenyl group, an optionally substituted aralkyl group or a hydrogenatom, or

two R¹s, which are bonded to the same carbon atom, are bonded to form aring together with the carbon atom to which they are bonded,

R² represents a C1-6 alkyl group, an optionally substituted phenyl groupor an optionally substituted aralkyl group, n represents an integer of 0to 3, and * represents an asymmetric center.

Another embodiment relates to a method for producing the above-mentionedoptically active cycloalkylidenebisamidoalcohol compound represented bythe formula (3), which comprises reacting an optically activeaminoalcohol compound represented by the formula (1):

wherein R¹, R² and * are as defined above, with a cycloalkylidenemalonicacid diester compound represented by the formula (2):

wherein R³ represents a C1-3 alkyl group and n represents an integer of0 to 3, in the presence of a lithium compound, and yet anotherembodiment relates to a method for producing an optically activecycloalkylidenebisoxazoline compound represented by the formula (4):

wherein R¹, R², n and * are as defined in the above formula (3), whichcomprises reacting the optically active cycloalkylidenebisamidoalcoholcompound represented by the formula (3) with a sulfonylation agent inthe presence of a basic compound.

BEST MODE FOR CARRYING OUT THE PRESENT INVENTION

The optically active aminoalcohol compound represented by the formula(1) (hereinafter, simply referred to as the optically activeaminoalcohol (1)) will be illustrated.

Examples of the C1-6 alkyl group represented by R¹ or R² in theoptically active aminoalcohol (1) include a straight or branched chainC1-6 alkyl group such as a methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, n-pentyl and n-hexyl group.

Examples of the optionally substituted phenyl group represented by R¹ orR² include a phenyl group which may be substituted with at least oneselected from a C1-6 alkyl group and a C1-6 alkoxy group such as anunsubstituted phenyl group; a phenyl group substituted with theabove-mentioned C1-6 alkyl group such as a 3-methylphenyl and4-methylphenyl group; and a phenyl group substituted with a C1-6 alkoxygroup (e.g. a methoxy, ethoxy, propoxy, butoxy, pentyloxy, and hexyloxygroup) such as a 2-methoxyphenyl and 4-methoxyphenyl group.

Examples of the optionally substituted aralkyl group represented by R¹or R² include an optionally substituted C7-16 aralkyl group (in moredetail, for example, a C1-6 alkyl group substituted with a naphthylgroup or an optionally substituted phenyl group). As the substituents ofthe optionally substituted C7-16 aralkyl group, at least one substituentselected from a C1-6 alkyl group and a C1-6 alkoxy group is exemplified.Specific examples of the optionally substituted aralkyl group include aC1-6 alkyl group substituted with a phenyl group which may besubstituted with a C1-6 alkyl group or a C1-6 alkoxy group, and a C1-6alkyl group substituted with a naphthyl group such as a benzyl,4-methylbenzyl, 4-methoxybenzyl, 1-naphthylmethyl and 2-naphthylmethylgroup.

As the ring formed by bonding two R¹s, which are bonded to the samecarbon atom, together with the carbon atom to which they are bonded,C3-6 cycloalkanes such as a cyclopropane ring, a cyclobutane ring, acyclopentane ring and a cyclohexane ring are exemplified.

Herein, Examples of the optically active aminoalcohol compound (1)include (R)-2-amino-propanol, (R)-2-amino-1,1-dimethylpropanol,(R)-2-amino-1,1-diethylpropanol, (R)-2-amino-1,1-di(n-propyl)propanol,(R)-2-amino-1,1-diphenylpropanol,(R)-2-amino-1,1-di(4-methylphenyl)propanol,(R)-2-amino-1,1-di(2-methoxyphenyl)propanol,(R)-2-amino-1,1-di(4-methoxyphenyl)propanol,(R)-2-amino-1,1-dibenzylpropanol, 1-((R)-1-aminoethyl)cyclobutanol,1-((R)-1-aminoethyl)cyclopentanol, 1-((R)-1-aminoethyl)cyclohexanol,

(R)-2-amino-3-methylbutanol, (R)-2-amino-3-methyl-1,1-dimethylbutanol,(R) -2-amino-3-methyl-1,1-diethylbutanol,(R)-2-amino-3-methyl-1,1-di(n-propyl)butanol,(R)-2-amino-3-methyl-1,1-diphenylbutanol,(R)-2-amino-3-methyl-1,1-di(4-methylphenyl)butanol,(R)-2-amino-3-methyl-1,1-di(2-methoxyphenyl)butanol,(R)-2-amino-3-methyl-1,1-di(4-methoxyphenyl)butanol,(R)-2-amino-3-methyl-1,1-dibenzylbutanol,1-((R)-1-amino-2-methylpropyl)cyclobutanol,1-((R)-1-amino-2-methylpropyl)cyclopentanol,1-((R)-1-amino-2-methylpropyl)cyclohexanol,

(R)-2-amino-4-methylpentanol, (R)-2-amino-4-methyl-1,1-dimethylpentanol,(R)-2-amino-4-methyl-1,1-diethylpentanol,(R)-2-amino-4-methyl-1,1-di(n-propyl)pentanol,(R)-2-amino-4-methyl-1,1-diphenylpentanol,(R)-2-amino-4-methyl-1,1-di(4-methylphenyl)pentanol,(R)-2-amino-4-methyl-1,1-di(2-methoxyphenyl)pentanol,(R)-2-amino-4-methyl-1,1-di(4-methoxyphenyl)pentanol,(R)-2-amino-4-methyl-1,1-dibenzylpentanol,1-((R)-1-amino-3-methylbutyl)cyclobutanol,1-((R)-1-amino-3-methylbutyl)cyclopentanol,1-((R)-1-amino-3-methylbutyl)cyclohexanol,

(R)-2-amino-3,3-dimethylbutanol,(R)-2-amino-3,3-dimethyl-1,1-dimethylbutanol,(R)-2-amino-3,3-dimethyl-1,1-diethylbutanol,(R)-2-amino-3,3-dimethyl-1,1-di(n-propyl)butanol,(R)-2-amino-3,3-dimethyl-1,1-diphenylbutanol,(R)-2-amino-3,3-dimethyl-1,1-di(4-methylphenyl)butanol,(R)-2-amino-3,3-dimethyl-1,1-di(2-methoxyphenyl)butanol,(R)-2-amino-3,3-dimethyl-1,1-di(4-methoxyphenyl)butanol,(R)-2-amino-3,3-dimethyl-1,1-dibenzylbutanol,1-((R)-1-amino-2,2-dimethylpropyl)cyclobutanol,1-((R)-1-amino-2,2-dimethylpropyl)cyclopentanol,1-((R)-1-amino-2,2-dimethylpropyl)cyclohexanol,

(R)-2-amino-2-phenylethanol, (R)-2-amino-2-phenyl-1,1-dimethylethanol,(R)-2-amino-2-phenyl-1,1-diethylethanol,(R)-2-amino-2-phenyl-1,1-di(n-propyl)ethanol,(R)-2-amino-2-phenyl-1,1-diphenylethanol,(R)-2-amino-2-phenyl-1,1-di(4-methylphenyl)ethanol,(R)-2-amino-2-phenyl-1,1-di(2-methoxyphenyl)ethanol,(R)-2-amino-2-phenyl-1,1-di(4-methoxyphenyl)ethanol,(R)-2-amino-2-phenyl-1,1-dibenzylethanol,1-((R)-1-amino-1-phenylmethyl)cyclobutanol,1-((R)-1-amino-1-phenylmethyl)cyclopentanol,1-((R)-1-amino-1-phenylmethyl)cyclohexanol,

(R)-2-amino-3-phenylpropanol, (R)-2-amino-3-phenyl-1,1-dimethylpropanol,(R)-2-amino-3-phenyl-1,1-diethylpropanol,(R)-2-amino-3-phenyl-1,1-di(n-propyl)propanol,(R)-2-amino-3-phenyl-1,1-diphenylpropanol,(R)-2-amino-3-phenyl-1,1-di(4-methylphenyl)propanol,(R)-2-amino-3-phenyl-1,1-di(2-methoxyphenyl)propanol,(R)-2-amino-3-phenyl-1,1-di(4-methoxyphenyl)propanol,(R)-2-amino-3-phenyl-1,1-dibenzylpropanol,1-((R)-1-amino-2-phenylethyl)cyclobutanol,1-((R)-1-amino-2-phenylethyl)cyclopentanol and1-((R)-1-amino-2-phenylethyl)cyclohexanol; and these compounds of which(R) corresponds to (S), and salts thereof such as salts ofhydrochloride, salts of sulfuric acid and salts of acetic acid.

The method for producing the above-mentioned optically activeaminoalcohol (1) is not particularly limited and for example, thoseobtained by a known method wherein an easily available optically activeamino acid type compound or the ester thereof represented by the formula(6) (hereinafter, simply referred to as the optically active amino acid(6)):

wherein R² and * are as defined above and R⁴ represents a C1-4 alkylgroup or a hydrogen atom, is a starting material, can be used.

Examples of the C1-4 alkyl group represented by R⁴ include a methyl,ethyl, n-propyl, isopropyl, n-butyl and tert-butyl group. Among theoptically active amino acid (6), examples of the optically active aminoacid ester include (R)-alanine methyl ester, (R)-valine methyl ester,(R)-leucine methyl ester, (R)-tert-leucine methyl ester,(R)-phenylglycine methyl ester, (R)-(1-naphthyl)glycine methyl ester,(R)-(2-naphthyl)glycine methyl ester, (R)-phenylalanine methyl ester,and these compounds in which the methyl group of the ester moiety isreplaced with an ethyl, propyl or n-butyl group; and these compounds ofwhich (R) corresponds to (S). Examples of the amino acid include(R)-alanine, (R)-valine, (R)-leucine, (R)-tert-leucine,(R)-phenylglycine, (R)-(1-naphthyl)glycine, (R)-(2-naphthyl)glycine,(R)-phenylalanine, and these compounds in which (R) corresponds to (S).Further, the optically active amino acid (6) include salts such as asalt of hydrochloride, a salt of sulfuric acid and a salt of acetic acidof the above-mentioned each compounds.

As the method for producing the optically active aminoalcohol (1)wherein the optically active amino acid (6) is the starting material,when R¹ in the formula (1) is the hydrogen atom, the reaction of theoptically active amino acid (6) and a borohydride compound isexemplified (e.g. Tetrahedron Letters, 33, 5517(1992), J. Org. Chem.,58, 3568(1993) and Angew. Chem. Int. Ed. Engl., 28, 218(1989)).

Herein, examples of the borohydride compound include boron hydride and acomplex of it and a compound which can be coordinated to it such asdiborane and borane-tetrahydrofuran complex; a mixture comprising ametal borohydride and an acid; a mixture comprising a metal borohydrideand a diester of sulfuric acid; and a metal borohydride. When the esterof the optically active amino acid (R⁴ is a alkyl group having 1 to 4carbon atoms) is used as the optically active amino acid (6), only themetal borohydride is preferably used as the borohydride compound. Whenthe optically active amino acid (R⁴ is a hydrogen atom) is used as theoptically active amino acid (5), at least one borohydride compoundselected from boron hydride and the complex of it and the compound whichcan be coordinated to it; the mixture comprising the metal borohydrideand the acid; the mixture comprising the metal borohydride and thesulfuric acid diester; and the metal borohydride is preferably used asthe borohydride compound.

Examples of the metal borohydride include lithium borohydride, sodiumborohydride, potassium borohydride and zinc borohydride, and sodiumborohydride is preferably used in terms of availability. Examples of theacid mixed with the metal borohydride include an inorganic acid such assulfuric acid and hydrochloric acid; and a Lewis acid such as borontrifluoride, zinc chloride, aluminum chloride, titanium tetrachloride,trimethylsilyl chloride and iodine. Examples of the diester of sulfuricacid include dimethyl sulfate and diethyl sulfate.

As the method for producing the optically active aminoalcohol (1)wherein R¹ in the formula (1) is the C1-6 alkyl group, the optionallysubstituted aralkyl group or the optionally substituted phenyl group,for example, a reaction of the optically active amino acid (6) whereinR⁴ in the formula (6) is the C1-4 alkyl group and a Grignard reagent isexemplified. Examples of the Grignard reagent include a Grignard reagentrepresented by the formula (7) (hereinafter, simply referred to as theGrignard reagent (7)):R¹MgX  (7)

wherein R¹ is as defined above and X represents a halogen atom, andexamples of the halogen atom represented by X include a chlorine atom, abromine atom and an iodine atom.

Examples of the Grignard reagent (7) include methylmagnesium chloride,ethylmagnesium chloride, n-propylmagnesium chloride, isopropylmagnesiumchloride, n-butylmagnesium chloride, isobutylmagnesium chloride,tert-butylmagnesium chloride, n-pentylmagnesium chloride,n-hexylmagnesium chloride, phenylmagnesium chloride,3-methylphenylmagnesium chloride, 4-methylphenylmagnesium chloride,2-methoxyphenylmagnesium chloride, 4-methoxyphenylmagnesium chloride,benzylmagnesium chloride, 4-methylbenzylmagnesium chloride,4-methoxybenzylmagnesium chloride, 1-naphthylmethylmagnesium chloride,2-naphthylmethylmagnesium chloride, and these compounds in which“chloride” is replaced with “bromide” or “iodide”. When R¹ representsC1-6 alkyl group and the compound in which two R¹s, which are bonded tothe same carbon atom, are bonded to form a ring together with the carbonatom to which they are bonded is desired, the Grignard reagent such asbutane-1,4-dimagnesium dichloride, pentane-1,5-dimagnesium dichloride,hexane-1,6-dimagnesium dichloride and these compounds in which“chloride” is replaced with “bromide” or “iodide” may be used as theGrignard reagent.

The configuration of the asymmetric center represented by * in theoptically active aminoalcohol (1) obtained is the same as that of theoptically active amino acid (6) used.

When n is 0 in the cycloalkylidenemalonic acid diester compoundrepresented by the formula (2) (hereinafter, simply referred to as thecycloalkylidenemalonic acid diester (2)), the cycloalkylidenemalonicacid diester (2) represents the cyclopropylidenemalonic acid diester.

Examples of the cycloalkylidenemalonic acid diester (2) include dimethylcyclopropane-1,1-dicarboxylate, diethyl cyclopropane-1,1-dicarboxylate,dimethyl cyclobutane-1,1-dicarboxylate, diethylcyclobutane-1,1-dicarboxylate, dimethyl cyclopentane-1,1-dicarboxylate,diethyl cyclopentane-1,1-dicarboxylate, dimethylcyclohexane-1,1-dicarboxylate and diethyl cyclohexane-1,1-dicarboxylate.As the cycloalkylidenemalonic acid diester (2) having a cyclopropanering, a cyclobutane ring, a cyclopentane ring or a cyclohexane ring, anyone of the methyl esters and the ethyl esters illustrated above iscommercially available.

A step for obtaining the optically active cycloalkylidenebisamidoalcoholcompound represented by the formula (3) (hereinafter, simply referred toas the optically active cycloalkylidenebisamidoalcohol (3)) by reactingthe cycloalkylidenemalonic acid diester (2) with the optically activeaminoalcohol (1) will be illustrated.

The reaction of the optically active aminoalcohol (1) and thecycloalkylidenemalonic acid diester (2) is usually carried out in thepresence of the lithium compound.

The amount of the cycloalkylidenemalonic acid diester (2) to be used isusually about 0.2 to 2 moles, preferably about 0.4 to 1 mole relative to1 mole of the optically active aminoalcohol compound (1).

Examples of the lithium compound used in the present invention includelithium hydroxide; a lithium alkoxide such as lithium methoxide andlithium ethoxide; and a lithium halide such as lithium chloride. Theamount of them to be used is not particularly limited and it may becatalytic amount and it is usually about 0.0005 to 0.5 mole relative to1 mole of the diester (2).

The reaction is usually carried out in the presence of a solvent.Examples of the solvent to be used include an aromatic hydrocarbonsolvent such as toluene and xylene; an aliphatic hydrocarbon solventsuch as hexane, heptane and octane; a halogenated hydrocarbon solventsuch as chlorobenzene; and an ether solvent such as tetrahydrofuran anddimethoxyethane. These solvents may be used alone or by mixing two ormore of them. The amount of the solvent to be used is not particularlylimited and it is usually about 2 to 500 parts by weight relative to 1part by weight of the optically active aminoalcohol compound (1).

The reaction temperature is not particularly limited and it is usually arange of about 20 to 150° C. The reaction is preferably carried outwhile removing an alcohol produced as a by-product in the reactionrepresented by the formula (5) (hereinafter, simply referred to as thealcohol (5):R³OH  (5)

wherein R³ is as above, out the reaction system at a temperature whichis a boiling point of the alcohol (5) and above.

The present reaction is usually carried out under an atmosphericcondition and may be carried out under a pressurized condition. It canbe also carried out under a reduced pressure in order to remove thealcohol (5) like the above.

The present reaction is carried out by mixing the lithium compound, theoptically active aminoalcohol (1) and the cycloalkylidenemalonic aciddiester (2), and if necessary in the presence of the solvent, and themixing order is not particularly limited. For example, it may be carriedout by adjusting a reaction temperature after mixing them at a time andby adding the cycloalkylidenemalonic acid diester (2) to a mixture ofthe lithium compound and the optically active aminoalcohol (1) which isadjusted to the reaction temperature.

After completion of the reaction, for example, the optically activecycloalkylidenebisamidoalcohol (3) can be obtained by adding water tothe reaction mixture, if necessary conducting extracting treatment usinga water-insoluble organic solvent such as toluene and ethyl acetate, andconcentrating the organic layer obtained. When the product isprecipitated from the reaction mixture, the product can be isolated bythe operation such as filtration. The optically activecycloalkylidenebisamidoalcohol (3) obtained can be further purified by aconventional method such as distillation and recrystallization.

The configuration of the asymmetric center represented by * in theoptically active cycloalkylidenebisamidoalcohol (3) thus obtained is thesame as that of the optically active aminoalcohol (1) used.

Examples of the optically active cycloalkylidenebisamidoalcohol (3)includeN,N′-bis[(R)-1-methyl-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1,2-dimethyl-2-hydroxypropyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2-ethyl-2-hydroxybutyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2-n-propyl-2-hydroxypentyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2,2-diphenyl-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2,2-di(4-methylphenyl)-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2,2-di(2-methoxyphenyl)-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2,2-di(4-methoxyphenyl)-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2-benzyl-2-hydroxy-3-phenylpropyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-(1-hydroxycyclobutyl)ethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-(1-hydroxycyclopentyl)ethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-(1-hydroxycyclohexyl)ethyl]cyclopropane-1,1-dicarboxamide,

N,N′-bis[(R)-1-isopropyl-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2-methyl-2-hydroxypropyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2-ethyl-2-hydroxybutyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2-n-propyl-2-hydroxypentyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2,2-diphenyl-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2,2-di(4-methylphenyl)-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2,2-di(2-methoxyphenyl)-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2,2-di(4-methoxyphenyl)-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2-benzyl-2-hydroxy-3-phenylpropyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-2-methyl-1-(1-hydroxycyclobutyl)propyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-2-methyl-1-(1-hydroxycyclopentyl)propyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-2-methyl-1-(1-hydroxycyclohexyl)propyl]cyclopropane-1,1-dicarboxamide,

N,N′-bis[(R)-1-isobutyl-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2-methyl-2-hydroxypropyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2-ethyl-2-hydroxybutyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2-n-propyl-2-hydroxypentyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2,2-diphenyl-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2,2-di(4-methylphenyl)-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2,2-di(2-methoxyphenyl)-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2,2-di(4-methoxyphenyl)-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2-benzyl-2-hydroxy-3-phenylpropyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-3-methyl-1-(1-hydroxycyclobutyl)butyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-3-methyl-1-(1-hydroxycyclopentyl)butyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-3-methyl-1-(1-hydroxycyclohexyl)butyl]cyclopropane-1,1-dicarboxamide,

N,N′-bis[(R)-1-tert-butyl-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2-methyl-2-hydroxypropyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2-ethyl-2-hydroxybutyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2-n-propyl-2-hydroxypentyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2,2-diphenyl-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2,2-di(4-methylphenyl)-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2,2-di(2-methoxyphenyl)-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2,2-di(4-methoxyphenyl)-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2-benzyl-2-hydroxy-3-phenylpropyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-2,2-dimethyl-1-(1-hydroxycyclobutyl)propyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-2,2-dimethyl-1-(1-hydroxycyclopentyl)propyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-2,2-dimethyl-1-(1-hydroxycyclohexyl)propyl]cyclopropane-1,1-dicarboxamide,

N,N′-bis[(R)-1-phenyl-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2-methyl-2-hydroxypropyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2-ethyl-2-hydroxybutyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2-n-propyl-2-hydroxypentyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2,2-diphenyl-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2,2-di(4-methylphenyl)-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2,2-di(2-methoxyphenyl)-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2,2-di(4-methoxyphenyl)-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2-benzyl-2-hydroxy-3-phenylpropyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-1-(1-hydroxycyclobutyl)methyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[R]-1-phenyl-1-(1-hydroxycyclopentyl)methyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-1-(1-hydroxycyclohexyl)methyl]cyclopropane-1,1-dicarboxamide,

N,N′-bis[(R)-1-benzyl-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2-methyl-2-hydroxypropyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2-ethyl-2-hydroxybutyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2-n-propyl-2-hydroxypentyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2,2-diphenyl-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2,2-di(4-methylphenyl)-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2,2-di(2-methoxyphenyl)-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2,2-di(4-methoxyphenyl)-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2-benzyl-2-hydroxy-3-phenylpropyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-2-phenyl-1-(1-hydroxycyclobutyl)ethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-2-phenyl-1-(1-hydroxycyclopentyl)ethyl]cyclopropane-1,1-dicarboxamide,N,N′-bis[(R)-2-phenyl-1-(1-hydroxycyclohexyl)ethyl]cyclopropane-1,1-dicarboxamide,

N,N′-bis[(R)-1-methyl-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1,2-dimethyl-2-hydroxypropyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2-ethyl-2-hydroxybutyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2-n-propyl-2-hydroxypentyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2,2-diphenyl-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2,2-di(4-methylphenyl)-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2,2-di(2-methoxyphenyl)-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2,2-di(4-methoxyphenyl)-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2-benzyl-2-hydroxy-3-phenylpropyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-(1-hydroxycyclobutyl)ethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-(1-hydroxycyclopentyl)ethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-(l-hydroxycyclohexyl)ethyl]cyclobutane-1,1-dicarboxamide,

N,N′-bis[(R)-1-isopropyl-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2-methyl-2-hydroxypropyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2-ethyl-2-hydroxybutyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2-n-propyl-2-hydroxypentyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2,2-diphenyl-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2,2-di(4-methylphenyl)-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2,2-di(2-methoxyphenyl)-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2,2-di(4-methoxyphenyl)-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2-benzyl-2-hydroxy-3-phenylpropyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-2-methyl-1-(1-hydroxycyclobutyl)propyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-2-methyl-1-(1-hydroxycyclopentyl)propyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-2-methyl-1-(1-hydroxycyclohexyl)propyl]cyclobutane-1,1-dicarboxamide,

N,N′-bis[(R)-1-isobutyl-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2-methyl-2-hydroxypropyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2-ethyl-2-hydroxybutyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2-n-propyl-2-hydroxypentyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2,2-diphenyl-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2,2-di(4-methylphenyl)-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2,2-di(2-methoxyphenyl)-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2,2-di(4-methoxyphenyl)-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2-benzyl-2-hydroxy-3-phenylpropyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-3-methyl-1-(1-hydroxycyclobutyl)butyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-3-methyl-1-(1-hydroxycyclopentyl)butyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-3-methyl-1-(1-hydroxycyclohexyl)butyl]cyclobutane-1,1-dicarboxamide,

N,N′-bis[(R)-1-tert-butyl-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2-methyl-2-hydroxypropyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2-ethyl-2-hydroxybutyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2-n-propyl-2-hydroxypentyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2,2-diphenyl-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2,2-di(4-methylphenyl)-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2,2-di(2-methoxyphenyl)-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2,2-di(4-methoxyphenyl)-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2-benzyl-2-hydroxy-3-phenylpropyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-2,2-dimethyl-1-(1-hydroxycyclobutyl)propyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-2,2-dimethyl-1-(1-hydroxycyclopentyl)propyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-2,2-dimethyl-1-(1-hydroxycyclohexyl)propyl]cyclobutane-1,1-dicarboxamide,

N,N′-bis[(R)-1-phenyl-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2-methyl-2-hydroxypropyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2-ethyl-2-hydroxybutyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2-n-propyl-2-hydroxypentyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2,2-diphenyl-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2,2-di(4-methylphenyl)-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2,2-di(2-methoxyphenyl)-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2,2-di(4-methoxyphenyl)-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2-benzyl-2-hydroxy-3-phenylpropyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-1-(1-hydroxycyclobutyl)methyllcyclobutane-1,1-dicarboxamide,N,N′-bis[R]-1-phenyl-1-(1-hydroxycyclopentyl)methyl]cyclobutane-1,1-dicarboxamide,N,N′-bis((R)-1-phenyl-1-(1-hydroxycyclohexyl)methyl]cyclobutane-1,1-dicarboxamide,

N,N′-bis[(R)-1-benzyl-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2-methyl-2-hydroxypropyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2-ethyl-2-hydroxybutyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2-n-propyl-2-hydroxypentyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2,2-diphenyl-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2,2-di(4-methylphenyl)-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2,2-di(2-methoxyphenyl)-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2,2-di(4-methoxyphenyl)-2-hydroxyethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2-benzyl-2-hydroxy-3-phenylpropyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-2-phenyl-1-(1-hydroxycyclobutyl)ethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-2-phenyl-1-(1-hydroxycyclopentyl)ethyl]cyclobutane-1,1-dicarboxamide,N,N′-bis[(R)-2-phenyl-1-(1-hydroxycyclohexyl)ethyl]cyclobutane-1,1-dicarboxamide,

N,N′-bis[(R)-1-methyl-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1,2-dimethyl-2-hydroxypropyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2-ethyl-2-hydroxybutyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2-n-propyl-2-hydroxypentyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2,2-diphenyl-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2,2-di(4-methylphenyl)-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2,2-di(2-methoxyphenyl)-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2,2-di(4-methoxyphenyl)-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2-benzyl-2-hydroxy-3-phenylpropyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-(1-hydroxycyclobutyl)ethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-(1-hydroxycyclopentyl)ethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-(1-hydroxycyclohexyl)ethyl]cyclopentane-1,1-dicarboxamide,

N,N′-bis[(R)-1-isopropyl-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2-methyl-2-hydroxypropyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2-ethyl-2-hydroxybutyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2-n-propyl-2-hydroxypentyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2,2-diphenyl-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2,2-di(4-methylphenyl)-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2,2-di(2-methoxyphenyl)-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2,2-di(4-methoxyphenyl)-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2-benzyl-2-hydroxy-3-phenylpropyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-2-methyl-1-(1-hydroxycyclobutyl)propyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-2-methyl-1-(1-hydroxycyclopentyl)propyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-2-methyl-1-(1-hydroxycyclohexyl)propyl]cyclopentane-1,1-dicarboxamide,

N,N′-bis[(R)-1-isobutyl-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2-methyl-2-hydroxypropyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2-ethyl-2-hydroxybutyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2-n-propyl-2-hydroxypentyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2,2-diphenyl-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2,2-di(4-methylphenyl)-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2,2-di(2-methoxyphenyl)-2-hydroxyethyllcyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2,2-di(4-methoxyphenyl)-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2-benzyl-2-hydroxy-3-phenylpropyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-3-methyl-1-(1-hydroxycyclobutyl)butyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-3-methyl-1-(1-hydroxycyclopentyl)butyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-3-methyl-1-(1-hydroxycyclohexyl)butyl]cyclopentane-1,1-dicarboxamide,

N,N′-bis[(R)-1-tert-butyl-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2-methyl-2-hydroxypropyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2-ethyl-2-hydroxybutyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2-n-propyl-2-hydroxypentyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2,2-diphenyl-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2,2-di(4-methylphenyl)-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2,2-di(2-methoxyphenyl)-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2,2-di(4-methoxyphenyl)-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2-benzyl-2-hydroxy-3-phenylpropyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-2,2-dimethyl-1-(1-hydroxycyclobutyl)propyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-2,2-dimethyl-1-(1-hydroxycyclopentyl)propyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-2,2-dimethyl-1-(1-hydroxycyclohexyl)propyl]cyclopentane-1,1-dicarboxamide,

N,N′-bis[(R)-1-phenyl-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2-methyl-2-hydroxypropyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2-ethyl-2-hydroxybutyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2-n-propyl-2-hydroxypentyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2,2-diphenyl-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2,2-di(4-methylphenyl)-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2,2-di(2-methoxyphenyl)-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2,2-di(4-methoxyphenyl)-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2-benzyl-2-hydroxy-3-phenylpropyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-1-(1-hydroxycyclobutyl)methyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[R]-1-phenyl-1-(1-hydroxycyclopentyl)methyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-1-(1-hydroxycyclohexyl)methyl]cyclopentane-1,1-dicarboxamide,

N,N′-bis[(R)-1-benzyl-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2-methyl-2-hydroxypropyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2-ethyl-2-hydroxybutyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2-n-propyl-2-hydroxypentyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2,2-diphenyl-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2,2-di(4-methylphenyl)-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2,2-di(2-methoxyphenyl)-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2,2-di(4-methoxyphenyl)-2-hydroxyethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2-benzyl-2-hydroxy-3-phenylpropyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-2-phenyl-1-(1-hydroxycyclobutyl)ethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-2-phenyl-1-(1-hydroxycyclopentyl)ethyl]cyclopentane-1,1-dicarboxamide,N,N′-bis[(R)-2-phenyl-1-(1-hydroxycyclohexyl)ethyl]cyclopentane-1,1-dicarboxamide,

N,N′-bis[(R)-1-methyl-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1,2-dimethyl-2-hydroxypropyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2-ethyl-2-hydroxybutyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2-n-propyl-2-hydroxypentyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2,2-diphenyl-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2,2-di(4-methylphenyl)-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2,2-di(2-methoxyphenyl)-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2,2-di(4-methoxyphenyl)-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-methyl-2-benzyl-2-hydroxy-3-phenylpropyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-(1-hydroxycyclobutyl)ethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-(1-hydroxycyclopentyl)ethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-(1-hydroxycyclohexyl)ethyl]cyclohexane-1,1-dicarboxamide,

N,N′-bis[(R)-1-isopropyl-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2-methyl-2-hydroxypropyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2-ethyl-2-hydroxybutyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2-n-propyl-2-hydroxypentyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2,2-diphenyl-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2,2-di(4-methylphenyl)-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2,2-di(2-methoxyphenyl)-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2,2-di(4-methoxyphenyl)-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-isopropyl-2-benzyl-2-hydroxy-3-phenylpropyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-2-methyl-1-(1-hydroxycyclobutyl)propyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-2-methyl-1-(1-hydroxycyclopentyl)propyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-2-methyl-1-(1-hydroxycyclohexyl)propyl]cyclohexane-1,1-dicarboxamide,

N,N′-bis[R-1-isobutyl-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2-methyl-2-hydroxypropyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2-ethyl-2-hydroxybutyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2-n-propyl-2-hydroxypentyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2,2-diphenyl-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2,2-di(4-methylphenyl)-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2,2-di(2-methoxyphenyl)-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2,2-di(4-methoxyphenyl)-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-isobutyl-2-benzyl-2-hydroxy-3-phenylpropyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-3-methyl-1-(1-hydroxycyclobutyl)butyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-3-methyl-1-(1-hydroxycyclopentyl)butyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-3-methyl-1-(1-hydroxycyclohexyl)butyl]cyclohexane-1,1-dicarboxamide,

N,N′-bis[(R)-1-tert-butyl-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2-methyl-2-hydroxypropyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2-ethyl-2-hydroxybutyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2-n-propyl-2-hydroxypentyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2,2-diphenyl-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2,2-di(4-methylphenyl)-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2,2-di(2-methoxyphenyl)-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2,2-di(4-methoxyphenyl)-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-tert-butyl-2-benzyl-2-hydroxy-3-phenylpropyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-2,2-dimethyl-1-(1-hydroxycyclobutyl)propyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-2,2-dimethyl-1-(1-hydroxycyclopentyl)propyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-2,2-dimethyl-1-(1-hydroxycyclohexyl)propyl]cyclohexane-1,1-dicarboxamide,

N,N′-bis[(R)-1-phenyl-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2-methyl-2-hydroxypropyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2-ethyl-2-hydroxybutyllcyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2-n-propyl-2-hydroxypentyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2,2-diphenyl-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2,2-di(4-methylphenyl)-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2,2-di(2-methoxyphenyl)-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2,2-di(4-methoxyphenyl)-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-2-benzyl-2-hydroxy-3-phenylpropyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-1-(1-hydroxycyclobutyl)methyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[R]-1-phenyl-1-(1-hydroxycyclopentyl)methyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-phenyl-1-(1-hydroxycyclohexyl)methyl]cyclohexane-1,1-dicarboxamide,

N,N′-bis[(R)-1-benzyl-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2-methyl-2-hydroxypropyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2-ethyl-2-hydroxybutyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2-n-propyl-2-hydroxypentyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2,2-diphenyl-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2,2-di(4-methylphenyl)-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2,2-di(2-methoxyphenyl)-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2,2-di(4-methoxyphenyl)-2-hydroxyethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-1-benzyl-2-benzyl-2-hydroxy-3-phenylpropyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-2-phenyl-1-(1-hydroxycyclobutyl)ethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-2-phenyl-1-(1-hydroxycyclopentyl)ethyl]cyclohexane-1,1-dicarboxamide,N,N′-bis[(R)-2-phenyl-1-(1-hydroxycyclohexyl)ethyl]cyclohexane-1,1-dicarboxamide;and these compounds of which the configuration (R) is changed to (S).

Next, a step for obtaining the optically activecycloalkylidenebisoxazoline compound represented by the formula (4)(hereinafter, described as the optically activecycloalkylidenebisoxazoline (4)) by reacting the optically activecycloalkylidenebisamidoalcohol (3) with the sulfonylation agent in thepresence of a basic compound.

Examples of the basic compound include an organic amine compound such aspyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine andtriethylamine; an alkali metal hydroxide such as sodium hydroxide andpotassium hydroxide; and an alkali metal alkoxide such as sodiummethoxide and potassium tert-butoxide. These basic compounds may be usedalone and any two or more compounds may be used at the same time. Theamount of the basic compound to be used is not particularly limited andlarge excess thereof may be used as the solvent. The amount thereof isusually about 0.0005 to 5 moles relative to 1 mole of the opticallyactive cycloalkylidenebisamidoalcohol (3). When two or more compoundsare used at the same time, this amount is sum of number of molesthereof.

The sulfonylation agent represents at least one compound selected fromthe group consisting of alkylsulfonyl halides, arylsulfonyl halides,alkylsulfonyl anhydrides and arylsulfonyl anhydrides.

Examples of alkylsulfonyl halides include compounds having 1 to 5 carbonatoms having an optionally substituted alkyl group such asmethanesulfonyl chloride, methanesulfonyl bromide, ethanesulfonylchloride and ethanesulfonyl bromide. Examples of arylsulfonyl halidesinclude C6-10 compounds having an optionally substituted aryl group suchas benzenesulfonyl chloride, benzensulfonyl bromide, paratoluenesulfonylchloride and paratoluenesulfonyl bromide. Examples of alkylsulfonylanhydrides include C2-20 compounds having an optionally substitutedalkyl group such as methanesulfonyl anhydride, ethanesulfonyl anhydrideand trifluoromethanesulfonyl anhydride. Examples of arylsulfonylanhydrides include C12-20 compounds having an optionally substitutedaryl group such as benzenesulfonyl anhydride and paratoluenesulfonylanhydride. Among these sulfonylation agents, methanesulfonyl chlorideand paratoluenesulfonyl chloride are preferably used.

The amount of the sulfonylation agent to be used is usually about 1 to 5moles relative to 1 mole of the optically activecycloalkylidenebisamidoalcohol (3).

The reaction is usually carried out in the presence of a solvent. Thesolvent is not particularly limited and examples thereof includearomatic hydrocarbon solvents such as toluene and xylene; halogenatedhydrocarbon solvents such as chlorobenzene, dichloromethane anddichloroethane; ether solvents such as tetrahydrofuran and tert-butylmethyl ether; and a mixture thereof. The amount thereof is notparticularly limited and it is usually 2 to 200 parts by weight relativeto 1 part by weight of the optically activecycloalkylidenebisamidoalcohol (3).

The reaction temperature is usually a range of about −20 to 150° C.,preferably a range of about 0 to 100° C.

After completion of the reaction, for example, the optically activecycloalkylidenebisoxazoline (4) can be obtained by concentrating thereaction liquid obtained. The optically activecycloalkylidenebisoxazoline (4) obtained can be purified by aconventional method such as column chromatography and recrystallization,if necessary.

The configuration of the asymmetric center represented by * in theoptically active cycloalkylidenebisoxazoline (4) thus obtained is thesame as that of the optically active cycloalkylidenebisamidoalcohol (3)used.

Examples of the optically active cycloalkylidenebisoxazoline (4) include1,1-bis[2-[(4R)-methyloxazoline]]cyclopropane,1,1-bis[2-[(4R)-methyl-5,5-dimethyloxazoline]]cyclopropane,1,1-bis[2-[(4R)-methyl-5,5-diethyloxazoline]]cyclopropane,1,1-bis[2-[(4R)-methyl-5,5-di-n-propyloxazoline]]cyclopropane,1,1-bis[2-[(4R)-methyl-5,5-diphenyloxazoline]]cyclopropane,1,1-bis[2-[(4R)-methyl-5,5-di(4-methylphenyl)oxazoline]]cyclopropane,1,1-bis[2-[(4R)-methyl-5,5-di(2-methoxyphenyl)oxazoline]]cyclopropane,1,1-bis[2-[(4R)-methyl-5,5-di(2-methoxyphenyl)oxazoline]]cyclopropane,1,1-bis[2-[(4R)-methyl-5,5-di(4-methoxyphenyl)oxazoline]]cyclopropane,1,1-bis[2-[(4R)-methyl-5,5-dibenzyloxazoline]]cyclopropane,1,1-bis[2-[spiro[(4R)-methyloxazoline-5,1′-cyclobutane]]]cyclopropane,1,1-bis[2-[spiro[(4R)-methyloxazoline-5,1′-cyclopentane]]]cyclopropane,1,1-bis[2-[spiro[(4R)-methyloxazoline-5,1′-cyclohexane]]]cyclopropane,

1,1-bis[2-[(4R)-isopropyloxazoline]]cyclopropane,1,1-bis[2-[(4R)-isopropyl-5,5-dimethyloxazoline]]cyclopropane,1,1-bis[2-[(4R)-isopropyl-5,5-diethyloxazoline]]cyclopropane,1,1-bis[2-[(4R)-isopropyl-5,5-di-n-propyloxazoline]]cyclopropane,1,1-bis[2-[(4R)-isopropyl-5,5-diphenyloxazoline]]cyclopropane,1,1-bis[2-[(4R)-isopropyl-5,5-di(4-methylphenyl)oxazoline]]cyclopropane,1,1-bis[2-[(4R)-isopropyl-5,5-di(2-methoxyphenyl)oxazoline]]cyclopropane,1,1-bis[2-[(4R)-isopropyl-5,5-di(2-methoxyphenyl)oxazoline]]cyclopropane,1,1-bis[2-[(4R)-isopropyl-5,5-di(4-methoxyphenyl)oxazoline]]cyclopropane,1,1-bis[2-[(4R)-isopropyl-5,5-dibenzyloxazoline]]cyclopropane,1,1-bis[2-[spiro[(4R)-isopropyloxazoline-5,1′-cyclobutane]]]cyclopropane,1,1-bis[2-[spiro[(4R)-isopropyloxazoline-5,1′-cyclopentane]]]cyclopropane,1,1-bis[2-[spiro[(4R)-isopropyloxazoline-5,1′-cyclohexane]]]cyclopropane,

1,1-bis[2-[(4R)-tert-butyloxazoline]]cyclopropane,1,1-bis[2-[(4R)-tert-butyl-5,5-dimethyloxazoline]]cyclopropane,1,1-bis[2-[(4R)-tert-butyl-5,5-diethyloxazoline]]cyclopropane,1,1-bis[2-[(4R)-tert-butyl-5,5-di-n-propyloxazoline]]cyclopropane,1,1-bis[2-[(4R)-tert-butyl-5,5-diphenyloxazoline]]cyclopropane,1,1-bis[2-[(4R)-tert-butyl-5,5-di(4-methylphenyl)oxazoline]]cyclopropane,1,1-bis[2-[(4R)-tert-butyl-5,5-di(2-methoxyphenyl)oxazoline]]cyclopropane,1,1-bis[2-[(4R)-tert-butyl-5,5-di(2-methoxyphenyl)oxazoline]]cyclopropane,1,1-bis[2-[(4R)-tert-butyl-5,5-di(4-methoxyphenyl)oxazoline]]cyclopropane,1,1-bis[2-[(4R)-tert-butyl-5,5-dibenzyloxazoline]]cyclopropane,1,1-bis[2-[spiro[(4R)-tert-butyloxazoline-5,1′-cyclobutane]]]cyclopropane,1,1-bis[2-[spiro[(4R)-tert-butyloxazoline-5,1′-cyclopentane]]]cyclopropane,1,1-bis[2-[spiro[(4R)-tert-butyloxazoline-5,1′-cyclohexane]]]cyclopropane,

1,1-bis[2-[(4R)-phenyloxazoline]]cyclopropane,1,1-bis[2-[(4R)-phenyl-5,5-dimethyloxazoline]]cyclopropane,1,1-bis[2-[(4R)-phenyl-5,5-diethyloxazoline]]cyclopropane,1,1-bis[2-[(4R)-phenyl-5,5-di-n-propyloxazoline]]cyclopropane,1,1-bis[2-[(4R)-phenyl-5,5-diphenyloxazoline]]cyclopropane,1,1-bis[2-[(4R)-phenyl-5,5-di(4-methylphenyl)oxazoline]]cyclopropane,1,1-bis[2-[(4R)-phenyl-5,5-di(2-methoxyphenyl)oxazoline]]cyclopropane,1,1-bis[2-[(4R)-phenyl-5,5-di(2-methoxyphenyl)oxazoline]]cyclopropane,1,1-bis[2-[(4R)-phenyl-5,5-di(4-methoxyphenyl)oxazoline]]cyclopropane,1,1-bis[2-[(4R)-phenyl-5,5-dibenzyloxazoline]]cyclopropane,1,1-bis[2-[spiro[(4R)-phenyloxazoline-5,1′-cyclobutane]]]cyclopropane,1,1-bis[2-[spiro[(4R)-phenyloxazoline-5,1′-cyclopentane]]]cyclopropane,1,1-bis[2-[spiro[(4R)-phenyloxazoline-5,1′-cyclohexane]]]cyclopropane,

1,1-bis[2-[(4R)-benzyloxazoline]]cyclopropane,1,1-bis[2-[(4R)-benzyl-5,5-dimethyloxazoline]]cyclopropane,1,1-bis[2-[(4R)-benzyl-5,5-diethyloxazoline]]cyclopropane,1,1-bis[2-[(4R)-benzyl-5,5-di-n-propyloxazoline]]cyclopropane,1,1-bis[2-[(4R)-benzyl-5,5-diphenyloxazoline]]cyclopropane,1,1-bis[2-[(4R)-benzyl-5,5-di(4-methylphenyl)oxazoline]]cyclopropane,1,1-bis[2-[(4R)-benzyl-5,5-di(2-methoxyphenyl)oxazoline]]cyclopropane,1,1-bis[2-[(4R)-benzyl-5,5-di(2-methoxyphenyl)oxazoline]]cyclopropane,1,1-bis[2-[(4R)-benzyl-5,5-di(4-methoxyphenyl)oxazoline]]cyclopropane,1,1-bis[2-[(4R)-benzyl-5,5-dibenzyloxazoline]]cyclopropane,1,1-bis[2-[spiro[(4R)-benzyloxazoline-5,1′-cyclobutane]]]cyclopropane,1,1-bis[2-[spiro[(4R)-benzyloxazoline-5,1′-cyclopentane]]]cyclopropane,1,1-bis[2-[spiro[(4R)-benzyloxazoline-5,1′-cyclohexane]]]cyclopropane;and these compounds in which cross-linked ring structure at the2-position of the oxazoline ring is replaced with a cyclobutane,cyclopentane or cyclohexane ring; and these compounds of which theconfiguration (4S) at the 4-positon of the oxazoline ring is changed to(4R) such as 1,1-bis[2-[(4S)-methyloxazoline]]cyclopropane.

EXAMPLES

The present invention will be further illustrated in more detail byExamples. The present invention is not limited to these Examples.

Example 1

In a 100 mL Schlenk tube purged with nitrogen, 980 mg (7.14 mmol) of(R)-phenylglycinol, 565 mg (3.57 mmol) of dimethyl1,1-cyclopropanedicarboxylate, 6.8 mg (0.18 mmol) of lithium methoxideand 40 mL of normal heptane were mixed and the resulting mixture wasstirred at 100° C. for 3 hours. The homogeneous solution changed to awhite suspension as the reaction progresses. After that, reactionsolution was cooled to room temperature and filtered. The obtainedpowder was dried to obtain 1.19 g of a white powder ofN,N′-bis[(R)-1-phenyl-1-(1-hydroxycyclohexyl)methyl]cyclopropane-1,1-dicarboxamide.

Yield: 90% (based on dimethyl 1,1-cyclopropanedicarboxylate).

¹H-NMR (δ: ppm, CD₃S(O)CD₃ solvent, TMS standard) 8.64 (d, J=8.60 Hz,2H), 7.32-7.19 (m, 10H), 5.01 (s, 2H), 4.90 (q, 6.73 Hz, 2H), 3.59 (d,5.2 Hz, 4H), 1.30 (s, 4H)

Example 2

According to the same manner as that described in Example 1, 1.28 g of awhite powder ofN,N′-bis[(S)-1-tert-butyl-2-hydroxyethyl]cyclopropane-1,1-dicarboxamidewas obtained except that 980 mg (8.36 mmol) of (S)-tert-leucinol, 655 mg(4.14 mmol) of dimethyl 1,1-cyclopropanedicarboxylate and 7.9 mg (0.21mmol) of lithium methoxide were used as each reaction agent.

Yield: 94% (based on dimethyl 1,1-cyclopropanedicarboxylate).

¹H-NMR (δ: ppm, CD₃S(O)CD₃ solvent, TMS standard) 7.76 (d, J=9.56 Hz,2H), 4.58 (t, J=5.20 Hz, 2H), 3.72 (dt, J=9.34 Hz, J=3.50 Hz, 2H),3.63-3.57 (m, 2H), 3.41-3.34 (m, 2H), 1.29-1.23 (m, 2H), 1.10-1.05 (m,2H), 0.82 (s, 18H)

Example 3

According to the same manner as that described in Example 2, 640 mg of awhite powder ofN,N′-bis[(S)-1-tert-butyl-2-hydroxyethyl]cyclopropane-1,1-dicarboxamidewas obtained except that 507 mg (4.32 mmol) of (S)-tert-leucinol, 342 mg(2.16 mmol) of dimethyl 1,1-cyclopropanedicarboxylate and 4.5 mg (0.11mmol) of lithium hydroxide monohydrate were used as each reaction agent.

Yield: 90% (based on dimethyl 1,1-cyclopropanedicarboxylate).

Example 4

According to the same manner as that described in Example 2, 1.38 g of awhite powder ofN,N′-bis[(S)-1-tert-butyl-2-hydroxyethyl]cyclohexane-1,1-dicarboxamidewas obtained except that 945 mg (4.14 mmol) of diethyl1,1-cyclohexanedicarboxylate was used in place of dimethyl1,1-cyclopropanedicarboxylate used in Example 2.

Yield: 90% (based on dimethyl 1,1-cyclohexanedicarboxylate).

¹H-NMR (δ: ppm, CD₃S(O)CD₃ solvent, TMS standard) 6.96 (d, J=9.49 Hz,2H), 4.48 (t, J=5.68 Hz, 2H), 3.77-3.70 (m, 2H), 3.59-3.52 (m, 2H),3.44-3.35 (m, 2H), 1.98-1.95 (m, 4H), 1.45-1.37 (m, 6H), 0.83 (s, 18H)

Comparative Example 1

According to the same manner as that described in Example 3, thereaction did not proceed and (S)-tert-leucinol and dimethylcyclopropanedicarboxylate, which are starting materials, were recoveredexcept that lithium methoxide was not used in Example 3.

Example 5

In a 100 mL Schlenk tube purged with nitrogen, 490 mg (1.49 mmol) ofN,N′-bis[(S)-1-tert-butyl-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide,664 mg (6.56 mmol) of triethylamine, 18.2 mg (0.15 mmol) of4-dimethylaminopyridine and 30 mL of dichloromethane were mixed and ahomogeneous solution was obtained. The solution was cooled to 0° C.After 345 mg (3.01 mmol) of methanesulfonyl chloride was added dropwiseto the solution over 10 minutes at the same temperature, the resultingmixture was heated to 20° C. and stirred for 12 hours. After a saturatedaqueous ammonium chloride solution was added thereto and stirred for 10minutes at room temperature, the separation was conducted to obtain theoil layer. After the oil layer was washed with 20 mL of a saturatedaqueous sodium hydrogen carbonate solution, a separation was conducted.The oil layer was dried over 5 g of anhydrous sodium sulfate. Thisreaction liquid was filtered and the obtained filtrate was concentrated.The residue was purified by column chromatography (alumina neutral,hexane:ethyl acetate=10:1 (v/v)) to yield 339 mg of a white powder of1,1-bis[2-[(4S)-tert-butyloxazoline]]cyclopropane.

Yield: 77%.

¹H-NMR (δ: ppm, CD₃Cl₃ solvent, TMS standard) 4.22-4.10 (m, 4H),3.85-3.79 (m, 2H), 1.52-1.48 (m, 2H), 1.29-1.24 (m, 2H), 0.86 (s, 18H)

Example 6

According to the same manner as that described in Example 5, 458 mg of awhite powder of 1,1-bis[2-[(4S)-tert-butyloxazoline]]cyclohexane wasobtained except that 552 mg (1.49 mmol) ofN,N′-bis[(S)-1-tert-butyl-2-hydroxyethyl]cyclohexane-1,1-dicarboxamidewas used in place of 490 mg (1.49 mmol) ofN,N′-bis[(S)-1-tert-butyl-2-hydroxyethyl]cyclopropane-1,1-dicarboxamideused in Example 5.

Yield: 92%.

¹H-NMR (δ: ppm, CD₃Cl₃ solvent, TMS standard) 4.16-4.02 (m, 4H),3.90-3.84 (m, 2H), 2.15-2.07 (m, 2H), 1.98-1.91 (m, 2H), 1.69-1.66 (m,2H), 1.55-1.42 (m, 4H), 0.89 (s, 18H)

Example 7-1 Synthesis of (S)-t-leucinol

To a 100 mL Schlenk tube purged with nitrogen, 2.00 g (15.3 mmol) of(S)-tert-leucine and 10 mL of tetrahydrofuran were added and the innertemperature was adjusted to 10° C. To this suspension, 30.5 mL (30.5mmol) of 1M borane-tetrahydrofuran solution was added dropwise over 30minutes and the resulting mixture was heated to an inner temperature of65° C. and stirred at the same temperature for 5 hours. After thereaction mixture was cooled to 10° C., 4 mL of methanol was addeddropwise thereto over 10 minutes. After reaction mixture wasconcentrated using an evaporator, 20 mL of 4M aqueous sodium hydroxidesolution was added thereto and stirred at room temperature for 1 hour.Next, the extraction was conducted by adding 30 mL of chloroform and theorganic layer obtained was dehydrated over sodium sulfate. Sodiumsulfate was removed by filtration and chloroform was distilled away byatmospheric distillation. Further, 1.43 g of (S)-tert-leucinol wasobtained as a fraction of 70 to 75° C. by reduced-pressure distillation(0.3 kPa).

Yield: 80%.

Example 7-2 Synthesis ofN,N′-bis[(S)-1-tert-butyl-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide

According to the same manner as that described in Example 2, 1.28 g of awhite powder ofN,N′-bis[(S)-1-tert-butyl-2-hydroxyethyl]cyclopropane-1,1-dicarboxamidewas obtained except that 980 mg (8.36 mmol) of (S)-tert-leucinolobtained in Example 7-1 was used.

Yield: 93% (based on dimethyl 1,1-cyclopropanedicarboxylate).

Example 7-3 Synthesis of1,1-bis[2-[(4S)-1-tert-butyloxazoline]]cyclopropane

According to the same manner as that described in Example 5, 344 mg of awhite powder of 1,1-bis[2-[(4S)-tert-butyloxazoline]]cyclopropane wasobtained except that 490 mg (1.49 mmol) ofN,N′-bis[(S)-1-tert-butyl-2-hydroxyethyl]cyclopropane-1,1-dicarboxamideobtained in Example 7-2 was used.

Yield: 79%.

Example 8-1 Synthesis of (S)-t-leucinol

To a 100 mL Schlenk tube purged with nitrogen, 4.00 g (30.5 mmol) of(S)-tert-leucine and 40 mL of tetrahydrofuran were added and the innertemperature was adjusted to 10° C. To this suspension, 1.46 g (61.0mmol) of lithium borohydride was added over 5 minutes and the innertemperature thereof was adjusted to 20° C. 7.44 g (67.1 mmol) oftrimethylsilyl chloride was added dropwise thereto over 30 minutes andthe mixture was heated to the inner temperature of 65° C. and stirred atthe same temperature for 3 hours. After the reaction mixture was cooledto 10° C., 4 mL of methanol was added dropwise thereto over 20 minutes.After reaction mixture was concentrated using an evaporator, 40 mL of 4Maqueous sodium hydroxide solution was added thereto and stirred at roomtemperature for 1 hour. Next, the extraction was conducted by adding 40mL of tert-butyl methyl ether and the organic layer obtained wasdehydrated over sodium sulfate. Sodium sulfate was removed by filtrationand tert-butyl methyl ether was distilled away by atmosphericdistillation. Further, 2.96 g of (S)-tert-leucinol was obtained as afraction of 70 to 75° C. by reduced-pressure distillation (0.3 kPa).

Yield: 83%.

Example 8-2 Synthesis ofN,N′-bis[(S)-1-tert-butyl-2-hydroxyethyl]cyclopropane-1,1-dicarboxamide

According to the same manner as that described in Example 2, 3.39 g of awhite powder ofN,N′-bis[(S)-1-tert-butyl-2-hydroxyethyl]cyclopropane-1,1-dicarboxamidewas obtained except that 2.55 g (21.8 mmol) of (S)-tert-leucinolobtained in Example 8-1, 1.72 g (10.9 mmol) of dimethyl1,1-cyclopropanedicarboxylate and 20.7 mg (0.54 mmol) of lithiummethoxide were used.

Yield: 95% (based on dimethyl 1,1-cyclopropanedicarboxylate).

Example 8-3 Synthesis of1,1-bis[2-[(4S)-tert-butyloxazoline]]cyclopropane

2.70 g (8.22 mmol) ofN,N′-bis[(S)-1-tert-butyl-2-hydroxyethyl]cyclopropane-1,1-dicarboxamideobtained in Example 8-2, 3.66 g (36.2 mmol) of triethylamine, 100 mg(0.82 mmol) of 4-dimethylaminopyridine and 30 mL of tetrahydrofuran wereadded and a homogeneous solution was obtained. The solution was cooledto 10° C. After 2.07 g (18.1 mmol) of methanesulfonyl chloride was addeddropwise thereto over 10 minutes at the same temperature, the resultingmixture was heated to 60° C. and stirred for 2 hours. After a saturatedaqueous ammonium chloride solution was added thereto and stirred for 10minutes at room temperature, the separation was conducted to obtain theoil layer. After the oil layer was washed with 20 mL of a saturatedaqueous sodium hydrogen carbonate solution, a separation was conductedto obtain the oil layer. The oil layer was dried over 5 g of anhydroussodium sulfate. This reaction liquid was filtered and the obtainedfiltrate was concentrated. The residue was purified by columnchromatography (alumina neutral, hexane:ethyl acetate=10:1 (v/v)) toyield 1.85 g of a white powder of1,1-bis[2-[(4S)-tert-butyloxazoline]]cyclopropane.

Yield: 77%.

Reference Example

In a 50 mL Schlenk tube purged with nitrogen, 6.47 mg (0.025 mmol) ofcopper(I) trifluoromethanesulfonate toluene complex, 8.00 mg of1,1-bis[2-[(4S)-tert-butyloxazoline]]cyclopropane and 5 mL ofdichloroethane were added and the resulting mixture was stirred at roomtemperature for 10 minutes to obtain a solution containing an asymmetriccopper complex. Then, 8.81 g (50 mmol) of isobutenylmethyl benzyl etherwas added thereto and the inner temperature was adjusted to 0° C. 10 mLof dichloroethane solution containing 2.85 g (25 mmol) of ethyldiazoacetate was added dropwise thereto over 2 hours and the resultingmixture was stirred at the same temperature for 30 minutes to effectreaction and the solution containing ethyl3,3-dimethyl-2-(benzyloxymethyl)cyclopropanecarboxylate was obtained.

Yield: 82% (based on ethyl diazoacetate).

Trans-isomer/cis-isomer ratio: 94/6.

(Herein, the trans-isomer means the compound having the ester group at1-position and benzyloxymethyl group at 2-position on the opposite sidewith respect to the cyclopropane ring plane and the cis-isomer means thecompound having the ester group at 1-position and benzyloxymethyl groupat 2-position on the same side.)

The reaction mixture was concentrated and a 1 g of the oily matterobtained was taken out. 4 mL of 2N aqueous sodium hydroxide was addedthereto and the resulting mixture was stirred at an inner temperature of100° C. for 2 hours. The neutralization by 1N hydrochloric acid, theextraction by hexane and the concentration were conducted to obtain3,3-dimethyl-2-benzyloxymethylcyclopropanecarboxylic acid.

Optical purity: trans-isomer 97% e.e. (+-isomer), cis-isomer 11% e.e.(+-isomer)

INDUSTRIAL APPLICABILITY

According to the present invention, an optically activecycloalkylidenebisoxazoline compound, which is an important compound asa ligand of an asymmetric synthesis catalyst, can be efficientlyproduced.

1. A method for producing the optically activecycloalkylidenebisamidoalcohol compound represented by the formula (3):

wherein R¹ represents a C1-6 alkyl group, an optionally substitutedphenyl group, an optionally substituted aralkyl group or a hydrogenatom, or two R¹s, which are bonded to the same carbon atom, are bondedto form a ring together with the carbon atom to which they are bonded,R² represents a C1-6 alkyl group, an optionally substituted phenyl groupor an optionally substituted aralkyl group, n represents an integer of 0to 3, and * represents an asymmetric center, which comprises reacting anoptically active aminoalcohol compound represented by the formula (1):

wherein R¹, R² and * are as defined above, with a cycloalkylidenemalonicacid diester compound represented by the formula (2):

wherein R³ represents a C1-3 alkyl group and n represents an integer of0 to 3, in the presence of a lithium compound.
 2. The method accordingto claim 1, which further comprises a step for obtaining an opticallyactive cycloalkylidenebisoxazoline compound represented by the formula(4):

wherein R¹ represents a C1-6 alkyl group, an optionally substitutedphenyl group, an optionally substituted aralkyl group or a hydrogenatom, or two R¹s, which are bonded to the same carbon atom, are bondedto form a ring together with the carbon atom to which they are bonded,R² represents a C1-6 alkyl group, an optionally substituted aralkylgroup or an optionally substituted phenyl group, n represents an integerof 0 to 3, and * represents an asymmetric center, by reacting theoptically active cycloalkylidenebisamidoalcohol compound represented bythe formula (3) with a sulfonylation agent in the presence of a basiccompound.
 3. The method according to claim 1, wherein the lithiumcompound is at least one lithium compound selected from lithiumhydroxide, a lithium alkoxide and a lithium halide.
 4. The methodaccording to claim 3, wherein the lithium alkoxide is lithium methoxideor lithium ethoxide.
 5. The method according to claim 3, wherein thelithium halide is lithium chloride.
 6. The method according to claim 1or 2, wherein the reaction is carried out while removing an alcoholproduced as a by-product represented by the formula (4):R³OH  (5) wherein R³ represents a C1-3 alkyl group.
 7. The methodaccording to claim 1, wherein the optically active aminoalcohol compoundrepresented by the formula (1) is the optically active aminoalcoholcompound obtained by reacting an optically active amino acid or theester thereof represented by the formula (6):

wherein R² represents a C1-6 alkyl group, an optionally substitutedaralkyl group or an optionally substituted phenyl group, R⁴ represents aC1-4 alkyl group or a hydrogen atom and * represents an asymmetriccenter, with a borohydride compound.
 8. The method according to claim 2,wherein the sulfonylation agent is paratoluenesulfonyl chloride ormethanesulfonyl chloride.
 9. The method according to claim 1 or 2,wherein R¹represents a C1-6 alkyl group; a phenyl group which may besubstituted with at least one selected from a C1-6 alkyl group and aC1-6 alkoxy group; a C7-16 aralkyl group which may be substituted withat least one substituent selected from a C1-6 alkyl group and a C1-6alkoxy group; or a hydrogen atom; or two R¹s, which are bonded to thesame carbon atom, are bonded to form a C3-6 cycloalkane together withthe carbon atom to which they are bonded, and R² represents a C1-6 alkylgroup; a phenyl group which may be substituted with at least oneselected from a C1-6 alkyl group and a C1-6 alkoxy group; or a C7-16aralkyl group which may be substituted with at least one substituentselected from a C1-6 alkyl group and a C1-6 alkoxy group.
 10. The methodaccording to claim 9, wherein R² represents a phenyl, 3-methylphenyl,4-methylphenyl, 2-methoxyphenyl or 4-methoxyphenyl group.